tbuckley/cabot-search huggingface dataset:
Detection of early-stage cancers using circulating orphan non-coding RNAs in blood.
Authors: Mehran Karimzadeh, Jeffrey Wang, Taylor B. Cavazos, Lee S. Schwartzberg, Michael Multhaup, Jeremy Ku, Xuan Zhao, Jieyang Wang, Kathleen Wang, Rose Hanna, Patrick Arensdorf, Kimberly H Chau, Helen Li, Hani Goodarzi, Lisa Fish, Fereydoun Hormozdiari, Babak Alipanahi
Journal: Journal of Clinical Oncology (2023)

3051 Background: Orphan non-coding RNAs (oncRNAs) are a novel category of small RNAs (smRNAs) that are present in tumors and largely absent in healthy tissue. We investigated the utility of oncRNAs extracted from serum for early cancer detection across seven cancer types. Methods: We collected 2,882 serum samples from individuals with known cancers of the bladder ( n=152), breast (220), colon and rectum (141), kidney (283), lung (281), pancreas (287), and stomach (280) as well as donors with no history of cancer (1,238). We used 0.5 mL serum aliquots to generate and sequence smRNA libraries at an average depth of 20 million 50-bp single-end reads. Samples were split into age-, sex-, and smoking status-matched training (1,232 cancer; 922 control) and validation (412 cancer; 316 control) cohorts. A large catalog of oncRNAs specific to each cancer was created using tumor and adjacent normal samples from The Cancer Genome Atlas (TCGA) smRNA-seq database. Using TCGA-derived oncRNAs, we trained a machine learning model to predict cancer presence and tissue of origin (TOO) in a 5-fold cross validation setup using our training cohort. For the validation cohort, we averaged the predictions from the five training cohort models. Results: The model ROC-AUC for detecting cancer was 0.95 (95% CI: 0.94–0.95 for training and 0.94–0.97 for validation cohorts). Sensitivities for detecting cancer at 95% specificity were 0.74 (0.70–0.76) for early stage (I/II) and 0.80 (0.76–0.84) for late stage (III/IV) cancers in the training cohort, and 0.77 (0.71–0.81) and 0.81 (0.73–0.87) in the validation cohort. Sensitivities of detection for each cancer type are shown. For samples with cancer and TOO predictions, our top 1 and top 2 TOO accuracy was 0.76 (0.68–0.84) and 0.83 (0.76–0.90) for the validation set. Conclusions: These results demonstrate that oncRNAs detected in serum can be used for accurate, early detection, and localization of multiple cancers. [Table: see text]
Selective recognition of over-expressed self-antigens in solid tumors using calibrated CAR-T therapy.
Authors: Farzad Haerizadeh, Helena Jiang, Laurence Cooper
Journal: Journal of Clinical Oncology (2023)

2540 Background: CAR-T has shown promise in patients with a subset of solid tumors. Future development depends on identifying CAR-T that differentiate between normal and malignant cells. The PrismCore platform develops CAR-T targeting self-antigens using three principles: 1) identification of targets uniformly expressed on solid tumors, 2) over-expression on the surface of invasive cancers compared to healthy cells, and 3) elevated levels linked to tumor aggressiveness. PrismCore produces CAR-T for treating multiple solid tumor types by calibrating T-cell activity against self-antigens only when present at elevated densities. Methods: PrismCore generates CAR-T by combining computational biology with empirical observations to target over-expressed self-antigens. Proto-libraries of CARs are created using synthetic single-domain antibodies and structural/signaling components. Bio-screening is performed using combinatorial libraries generated through computational simulation. Lead CAR-T are identified through iterative in vitro and in vivo testing and evaluated for safety in non-human primates (NHP). Results: PrismCore platform has identified engineered T cells against several self-antigens, with the first CAR-T, termed B4t2-001, advanced to clinical testing against the target BT-001. Libraries (1E10 to 1E11) of camelid antibodies were designed, synthesized, and assessed. Selected antibody variants subsets were combinatorially assembled into CAR-Ts and rigorously screened against gradient of BT-001. Six candidates were advanced to further testing in mice to evaluate anti-tumor effect and sustained in vivo biological activity. B4t2-001 was evaluated in NHP that express basal levels of BT-001. No toxicity observed despite measurable circulating CAR-T and in vitro activity to NHP BT-001 when at high density. The turnaround from target selection to B4t2-001 for clinical evaluation was six months. Conclusions: We report pre-clinical data for B4t2-001 that safely and effectively targets BT-001 when overexpressed on tumors. This is a novel target for T-cell therapy and is at elevated levels on multiple different types of solid tumors. BT-001 participates in pathobiology, tumor invasion as well as metastasis, and level of expression inversely correlates with overall survival. B4t2-001 demonstrated target density-dependent response, potency, durability of effect and safety in preclinical models and is undergoing phase I clinical evaluation (NCT05621486) in patients with different types of solid tumors. [Table: see text]
Pegylated liposomal doxorubicin combined with ifosfamide for advanced soft tissue sarcomas: A phase I dose-escalation study.
Authors: Ting Ye, Li Fan, Rubo Cao, Ling Peng, Jing Chen
Journal: Journal of Clinical Oncology (2023)

e23525 Background: Doxorubicin combined with ifosfamide (IFO) is one of the preferred treatment options for non-specific soft tissue sarcomas (STS), but is limited by cumulative cardiotoxicity and severe myelosuppression. Pegylated liposomal doxorubicin (PLD) provides an effective alternative to conventional anthracyclines with reduced toxicity. However, there is no standard dose recommendation for PLD combined with IFO for STS. The present study aimed to investigate the maximum tolerated dose (MTD) of PLD combined with IFO in advanced STS patients. Methods: This was a phase I, open-label, single-center, dose-escalation study. Patients with locally advanced or metastatic STS were enrolled, except for gastrointestinal stromal tumors, Ewing's sarcomas, embryonal rhabdomyosarcomas, and alveolar rhabdomyosarcomas. We used a standard 3 + 3 dose-escalation design with progressively increasing PLD and IFO (3 g/m 2 per day for 3 days, q3w) for one cycle, with a dose escalation ranged from 30 to 70 mg/m 2 (5mg/m 2 increment per step). The primary endpoint was determination of the MTD, and the secondary endpoint was the incidence/severity of adverse events (AEs). Results: From January 2020 to September 2022, 23 patients were enrolled in this study, including 3 patients at doses 30-45 mg/m 2 , 6 patients at dose 50 mg/m 2 , and 5 patients at 55 mg/m 2 . The median age was 49 years (ranges from 30 to 68 years), the male/female ratio was 12/11, and 22 (95.65%) patients had stage IV disease (AJCC staging system). Initially, no DLT was observed at doses of 30-50 mg/m 2 , with 3 patients in each dose phase. Two patients developed DLTs at the 55 mg/m 2 dose, resulting in the 50 mg/m 2 dose extending to a total of 6 patients who completed treatment without DLT. The DLTs at dose 55 mg/m 2 of the first patient were grade 4 neutropenia lasting ≥ 5 days and grade 3 thrombocytopenia with hemorrhage tendency; the second patient had grade 4 neutropenia lasting ≥ 5 days, grade 4 thrombocytopenia relapsed after platelet transfusion, and grade 3 increased alanine aminotransferase. Therefore, the MTD of PLD was 50 mg/m 2 . The most common (≥ 10%) grade 3-4 AEs in all patients were lymphopenia (56.52%), neutropenia (82.61%), leukopenia (86.96%), and thrombocytopenia (13.04%). Conclusions: For patients with locally advanced or metastatic STS, single cycle PLD combined with IFO had a tolerable AE profile, with an MTD of 50 mg/m 2 for PLD. Further researches are needed to confirm the multi-cycle recommendation. Clinical trial information: ChiCTR1900028270 .
Socio-demographic, clinical, and genetic predictors of low versus high Gleason score among men with prostate cancer in the Detroit Research on Cancer Survivorship (ROCS) cohort.
Authors: Samantha Goodenow, Frank Cameron Cackowski, Elisabeth I. Heath, Julie J. Ruterbusch, Greg Dyson, Jennifer Lynn Beebe-Dimmer, Michael S. Simon
Journal: Journal of Clinical Oncology (2023)

5092 Background: Black men with prostate cancer typically present with a higher Gleason Score (GS) and more aggressive disease than White men. The purpose of this project is to describe the relationship between socio-demographic, clinical and genomic variability with GS categories among 599 men with prostate cancer in the Detroit Research on Cancer Survivorship (ROCS) cohort. Methods: Detroit ROCS is a cohort of Black cancer survivors based in the Detroit Metropolitan area. Patient data was obtained from a self-administered questionnaire, cancer registry and biologic samples were collected through at home phlebotomy or mailed saliva kits. The primary analysis focused on clinical and genetic differences between men with GS ≤ 6 vs. ≥ 7. Germline data was compiled into the multi-ethnic genotyping array (MEGA) data panel and 21 genes were chosen for analysis (2,393 SNPS) based on their clinical applicability. Eight tools were used in ANNOtate VARiation (ANNOVAR) to determine whether a genetic variant was pathogenic. The determination of pathogenicity was defined by at least seven of the tools indicating variant pathogenicity. We assessed the rate of pathogenic variants for each GS category. Multivariable models of predictors of GS categories were conducted using logistic regression. Results: The categories across GS in the ROCS cohort included: ≤ 6 (21.2%), 3+4 (40.4%), 4+3 (20.2%) and ≥ 8 (18.2%). Variables associated with increased GS (≥ 7 vs. ≤ 6) included age (for each 10-year increase the OR was 1.71, 95% CI 1.26-2.34) and body mass index (for each 5 unit increase the OR was 1.27, 95% 1.06-1.54). Higher vs. lower education (some college education or higher vs less than or equal to a high school education) was associated with lower GS, OR 0.58, 95% CI 0.37-0.96. Out of a total of 2,393 SNPs analyzed, 880 (36.8%) were polymorphic, of which 684 had a minor allele frequency (MAF) &gt;0.001, and 282 had a MAF &gt;0.05. Overall, 16.2% of the men were carriers of a pathogenic variant, the most common of which were ATR (9.3%), FANCL (3.5%), and ATM (1.7). Men with GS 6 had a lower rate of pathogenic variants (8.7%), than those with GS 3+4 (18.2%), GS 4+3 (16.5%), and GS 8 (20.2%). Men with a pathogenic variant in ATR were 2.87 (95% CI 1.08- 7.65) times more likely to have GS ≥ 7 vs. ≤ 6. Higher GS was specifically associated with SNP rs33972295 in the ATR gene. Conclusions: The relationship between older age, higher BMI, and less educational background suggests that sociodemographic risk factors should be accounted for when assessing risk for higher grade prostate cancer. Identification of genomic differences associated with aggressive prostate cancer may provide insight into new targeted therapy options.
Early colorectal cancer detection with a spectroscopic liquid biopsy.
Authors: James Munro Cameron, Georgios Antoniou, Paul Brennan, Justin Conn, Ewan Gray, Sharon King, Rose McHardy, Susan Moug, Jennifer Nobes, David Palmer, Alexandra Sala, Benjamin Smith, Judith Strachan, Craig Mowat, Matthew Baker
Journal: Journal of Clinical Oncology (2023)

e15627 Background: Earlier diagnosis and treatment of colorectal cancer (CRC) maximizes the opportunity to combat or control disease progression. The average 5-year survival rate after diagnosis decreases from 91% in early-stage CRC, to as low as 15% for stage IV CRC. Furthermore, rapid detection and removal of pre-cancerous adenomas – e.g., advanced adenomas (AA) – can significantly improve survival rates of affected patients. However, current stool-based tests have inadequate AA sensitivities, such as FIT (24%) and FIT-DNA (42%). Liquid biopsies have great potential to supplement FIT tests and improve diagnostic pathways, but current blood tests based on tumor-derived biomarkers also have limited sensitivity for AA detection. Methods: The Dxcover® Cancer Liquid Biopsy is based on Fourier-transform infrared (FTIR) spectroscopy applied to serum from a standard blood sample. The spectral data are collected and analyzed using pattern recognition and machine learning algorithms to detect disease-specific signatures. We initially examined test performance for the detection of multiple cancer types. Additionally, we have analyzed a retrospective cohort of samples comprising 100 CRC, 99 AA removed by surgical resection and 97 colonoscopy screening controls. Results: The CRC classifier from the discovery multi-cancer dataset resulted in 74% sensitivity with 91% specificity when differentiating CRC and non-cancer, which surpasses the targets set by the Centers for Medicare &amp; Medicaid Services (CMS) for coverage of CRC tests. Receiver operating characteristic (ROC) analysis reported an area under the curve (AUC) value of 0.91. The machine learning algorithms can be fine-tuned to maximize either sensitivity or specificity depending on the requirements of different patient pathways. When tuned for higher sensitivity, the model produced 97% sensitivity (49% specificity), and when tailored for greater specificity (97%) the sensitivity was 47%. We have now progressed these findings to examine the ability of the technology to differentiate patients with CRC, AA and colonoscopy controls. Furthermore, we assess whether combining spectral data with additional clinical information, such as biomarker data and patient demographics, can enhance test performance. Conclusions: A rapid blood test that is sensitive to AA and early-stage CRC could improve patient prognosis and reduce cancer burden. With further development, this liquid biopsy could have a profound impact on the earlier detection of CRC.
Effects of treatment and patterns of metastases in upper tract and bladder urothelial cancer and non-urothelial cancer based on the national cancer database (NCDB) analysis.
Authors: Eun-mi Yu, Hongkun Wang, Jeanny B. Aragon-Ching
Journal: Journal of Clinical Oncology (2023)

e16571 Background: Upper tract Urothelial cancer (UTUC) and bladder urothelial and non-urothelial cancers can have varying patterns of metastases and response to treatment. Given worse response of visceral metastases to current immune checkpoint inhibitors (ICI) and worse outcomes of non-urothelial cancers, understanding the incidence, characteristics and survival for different metastatic presentation would be informative. Methods: The primary objective is to describe characteristics, treatment patterns, evaluate trends and differences in metastatic presentation and survival according to NCDB between upper tract urothelial cancers (UTUC) versus non-urothelial (nUTUC) histologies (squamous, sarcomatoid, small cell or neuroendocrine, adenocarcinoma) and bladder urothelial cancer (UC) and bladder non-urothelial cancer (nUC). Results: Extraction of data from diagnosis between year 2004 – 2017 from the NCDB was performed. A total of 649939 cases of whom UC = 630423 and nUC = 19516 for both bladder and upper tract cancers, respectively, were identified. Median age was 71.4 years (UC) and 70.1 years (nUC), with majority made up of men (62% of UTUC and 75% of bladder UC). Stage distribution at diagnosis was higher in nUC with Stage III at 1711 (8.8%, nUC) compared to 15725 (2.5%, UC) and Stage IV the nUC group (21.9%) compared to UC at 4.6%. Overall survival (OS) was worse with nUC for stage IV cancers with median OS (mOS) of 6.14 mos (95% CI 5.78-6.47) for nUC vs 7.92 mos (95% CI 7.75-8.08) for UC; logrank p &lt; 0.001. Metastatic sites evaluated included bone, brain, liver, lung, and distant lymph nodes. mOS of Patients with visceral metastatic sites of disease are as follows: distant lymph nodes: UC: 7.59 mos (95% CI 6.6- 8.8); nUC: 5.62 mos (95% CI 4.1-7); log-rank p = 0.0372; liver: UC: 3.5 mos (95% CI 2.89-4.1); nUC: 4.1 mos (95% CI 2.6-6.83); p = 0.1874; lung: UC: 5.7 mos (95% CI 5.09-6.37); nUC: 4.27 mos (95% CI 2.99-6.74); p = 0.1567; Brain: UC: 3.06 mos (95% CI 2.1-4.24); nUC: 2.34 (95% CI 1.1-5.3), p = 0.5464. Use of chemotherapy resulted in improved OS in the UC group with mOS of 73.53 mos (95% CI 72.61-74.41) compared to nUC at 17.28 mos (95% CI 16.59-17.87), p &lt; 0.0001 and use of ICI similarly yielded improvement in the UC group with mOS of 115.98 mos (95% CI 114.33-117.65) compared to nUC at 64.49 mos (95% CI 45.67-88.51); p &lt; 0.0001 although radiation therapy resulted in less profound treatment effect with UC at 16.39 mos (95% CI 16.07-16.69) and nUC: 13.01 (95% CI 12.32-13.63); p &lt; 0.0001. Conclusions: While treatment using chemotherapy and ICI has led to improvement in OS in higher stages of disease, patterns of metastases reveals visceral presentation portends a poor prognosis in both urothelial and non-urothelial cancers with slightly better mOS in those with distant lymph nodes as main presentation of metastases.
MagnetisMM-7: An open-label, multicenter, randomized phase 3 study of elranatamab versus lenalidomide in post-transplant patients with newly diagnosed multiple myeloma.
Authors: Maria Victoria Mateos Manteca, Sebastian Grosicki, Kihyun Kim, Eric Negre, Erik Vandendries
Journal: Journal of Clinical Oncology (2023)

TPS8066 Background: Elranatamab is a humanized bispecific antibody targeting B cell maturation antigen (BCMA) on myeloma cells and CD3 on T cells. Elranatamab has shown promising efficacy and acceptable safety in pts with relapsed and/or refractory multiple myeloma (MM). The aim of the MagnetisMM-7 study is to evaluate elranatamab monotherapy vs lenalidomide monotherapy in pts with newly diagnosed MM (NDMM) after undergoing autologous stem cell transplant (ASCT). Methods: MagnetisMM-7 is an ongoing, open-label, 2-arm, multicenter, randomized phase 3 study estimated to enroll ~700 pts. ClinicalTrials.gov ID: NCT05317416. Pts are randomized to receive either subcutaneous elranatamab or oral lenalidomide once daily. After initial step-up dosing, two alternative dosing regimens of elranatamab are examined. The primary endpoint is progression-free survival (PFS) assessed by blinded independent review per International Myeloma Working Group (IMWG) criteria (up to ~5 y). Secondary endpoints include overall survival, minimal residual disease (MRD) negativity rate at 12 mo after randomization per IMWG criteria as assessed via next-generation sequencing (NGS), sustained MRD negativity rate at 24 mo after randomization as assessed via NGS, PFS by investigator, duration of MRD negativity, complete response (CR) rate, duration of CR, safety, quality of life, immunogenicity, and pharmacokinetics. Key inclusion criteria are: ≥18 y; a diagnosis of MM with measurable disease according to IMWG criteria; history of induction therapy for NDMM, followed by high dose therapy and ASCT with or without consolidation; partial response or better according to IMWG criteria; identification of the dominant malignant clone; and Eastern Cooperative Oncology Group performance status ≤1. Randomization must occur ≤120 d from ASCT; for pts who receive consolidation therapy after ASCT, randomization must occur ≤60 d of consolidation and ≤7 mo of ASCT. Key exclusion criteria are: plasma cell leukemia; amyloidosis; Waldenström's macroglobulinemia; POEMS syndrome; known active CNS involvement or clinical signs of myelomatous meningeal involvement; previous MM maintenance treatment; prior treatment with BCMA-targeted therapy; any other active malignancy ≤3 y of enrollment; active, uncontrolled bacterial, fungal, or viral infection; and previous administration of an investigational drug or vaccine ≤30 d or 5 half-lives preceding the first dose of study treatment. As of February 2023, the study is open and enrolling at 29 sites in 13 countries. Clinical trial information: NCT05317416 .
Ancestry-adjusted genomic analysis to identify known and novel associations with single and multiple cancer phenotypes.
Authors: Vijai Joseph, Vignesh Ravichandran, Irina Ostrovnaya, Ying L Liu, Kaitlyn Tkachuk, Aliya Khurram, Yelena Kemel, Diana Mandelker, Chaitanya Bandlamudi, Michael Francis Walsh, Michael T Conry, Aijazuddin Syed, Nikolaus Schultz, David B. Solit, Michael F. Berger, Mark E. Robson, Zsofia Kinga Stadler, Kenneth Offit
Journal: Journal of Clinical Oncology (2023)

10504 Background: Germline cancer risks are impacted by cancer type, stage, specific mutation, and ancestry. This study aims to determine the magnitude of genetic risks for commonly tested genes across patients with single and multiple primary cancers (MPC). Methods: We conducted a partially de-identified, retrospective cohort study of all patients consented to using the MSK-IMPACT, a matched tumor-normal sequencing assay, over a five-year period. Approximately 83% of IMPACT testing is derived from patients with metastatic disease. We collected data on demographics and clinical cancer features through cBioPortal and institutional databases. MPC were classified based on the IARC guidelines. Clinically actionable, pathogenic variants in cases and gnomAD non-cancer controls were identified using PathoMAN. Statistical methods incorporated ancestry adjusted, weighted generalized linear model, and ancestry specific methods to estimate risk. Biallelic losses were analyzed from paired tumors. Results: We analyzed 28,000 individuals across 35 cancer types, where germline variants were discovered within 100 cancer predisposition genes. 16% carried pathogenic, clinically actionable variants in known and novel cancer predisposition genes (15% in those with single primary and 21% in MPC). We discovered statistically significant novel associations of germline variants with several cancer phenotypes, including BRCA2 and biliary cancer (OR = 4.5, CI = 2.2-8); ATM and BRCA2 with mesothelioma (OR = 4.8, CI = 2.1-9.2; OR = 8, CI = 3.1-16.6, respectively); NF1 and breast cancer (OR = 5.8, CI = 2.4-12.1); NBN and lung cancer (OR = 4.2, CI = 2.3-6.9), bladder with ATR and others. We replicated known associations and discovered pleiotropy of BRCA1/2, NF1, ATM, TP53 with several cancer types. We failed to replicate reported associations such as PALB2 and ovarian cancer and CHEK2 and colon cancer. Amongst cancer pairs of multiple primaries, we observed mismatch repair genes MSH2, MSH6 and MLH1 to be associated with increased risks for stomach, bowel, and uterine cancer pairs, and TP53 in breast MPC compared to breast single primaries. Conclusions: An ancestry adjusted, weighted analysis of a large real-world case-cohort enriched with metastatic disease did not confirm some prior genotype-phenotype correlations, while suggesting novel associations with hereditary cancer types.